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United States Patent |
5,332,826
|
Buckland
|
July 26, 1994
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Process for preparing aminoacetonitriles in one vessel
Abstract
This invention relates to a process for preparing aminoacetonitriles in one
vessel. The process involves the steps of: (A) reacting an alkali metal
cyanide with an aldehyde in water to form a cyanohydrin; (B) extracting
the cyanohydrin formed in Step (A) into a water immiscible solvent to form
a two phase system comprising a water immiscible phase containing the
cyanohydrin and an aqueous phase; (C) removing at least 50 weight percent,
based on the weight of the water immiscible phase, of the water immiscible
solvent from the water immiscible phase thereby concentrating the
cyanohydrin; (D) adding a water miscible amide solvent to the concentrated
cyanohydrin to form a cyanohydrin solution; and (E) passing ammonia
through the cyanohydrin solution to obtain an aminoacetonitrile.
Aminoacetonitriles are important intermediates in the preparation of amino
acids, thiadiazoles, acylaminoacetonitriles, and imidazole derivatives.
Inventors:
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Buckland; Paul R. (Rochester, NY)
|
Assignee:
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Eastman Kodak Company (Rochester, NY)
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Appl. No.:
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136432 |
Filed:
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October 13, 1993 |
Current U.S. Class: |
546/330; 549/74; 549/75; 549/491; 558/351; 558/408; 558/430; 558/432; 558/433; 558/434; 558/452 |
Intern'l Class: |
C07C 253/16; C07C 253/30; C07D 213/57 |
Field of Search: |
558/351,408,452
549/75,491
546/330
|
References Cited
U.S. Patent Documents
Re32952 | Jun., 1989 | Krepski et al. | 558/351.
|
4859784 | Aug., 1989 | Effenberger et al. | 558/351.
|
5169973 | Dec., 1992 | Gibson et al. | 558/351.
|
Other References
"Facile Synthesis of .alpha.-Aminonitriles", Khuong Mai et al, Tetrahedron
Letters vol. 25, No. 41, pp. 4583-4586, (1984).
"A Fast N-Substituted .alpha.-Aminonitrile Synthesis", Khuong Mai et al,
Synthetic Communications 15 (2), 157-163 (1985).
|
Primary Examiner: Brust; Joseph Paul
Attorney, Agent or Firm: Thallemer; John D.
Claims
What is claimed is:
1. A process for preparing aminoacetonitriles comprising the steps of:
(A) reacting an alkali metalcyanide with an aldehyde having the formula
RCHO at a temperature of -10.degree. C. to 25.degree. C. in water to form
a cyanohydrin, wherein R is selected from the group consisting of
hydrogen, C.sub.1 -C.sub.20 alkyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.3
-C.sub.8 alkenyl, C.sub.3 -C.sub.8 alkynyl, and C.sub.6 -C.sub.14 aryl,
excluding 3-nitrobenzaldehyde;
(B) adding a water immiscible solvent to the cyanohydrin formed in Step (A)
to form a two phase system comprising a water immiscible phase containing
the cyanohydrin and an aqueous phase;
(C) removing at least 50 weight percent, based on the weight of the water
immiscible phase, of the water immiscible solvent from the water
immiscible phase thereby concentrating the cyanohydrin;
(D) adding a water miscible amide solvent to the concentrated cyanohydrin
to form a cyanohydrin solution; and
(E) passing ammonia through the cyanohydrin solution to obtain an
aminoacetonitrile,
provided steps (B), (C), (D), and (E) are conducted at a temperature of
20.degree. C. to 50.degree. C, and further provided that steps (A), (B),
(C), (D), and (E) are conducted in the same reaction vessel wherein the
cyanohydrin is not isolated.
2. A process for preparing aminoacetonitriles comprising the steps of:
(A) reacting an alkali metal cyanide with an aldehyde at a temperature of
-10.degree. C. to 25.degree. C. in water to form a cyanohydrin, wherein
the alkali metal cyanide is selected from the group consisting of sodium
cyanide, potassium cyanide, lithium cyanide and cesium cyanide, and the
aldehyde is selected from the group consisting of p-anisaldehyde,
thiophene-2-carboxaldehyde, furan-2-carboxaldehyde, benzaldehyde,
crotonaldehyde, trimethylacetaldehyde, acetaldehyde, 4-methylbenzaldehyde,
4N,N-dimethylaminobenzaldehyde, 3-pyridinecarboxaldehyde, valeraldehyde,
and 2-chlorobenzaldehyde;
(B) adding a water immiscible solvent to the cyanohydrin formed in Step (A)
to from a two phase system comprising a water immiscible phase containing
the cyanohydrin and an aqueous phase, wherein the water immiscible solvent
is selected from the group consisting of dichloromethane, ethyl acetate,
diethyl ether, chloroform, 1,2-dichloroethane, methyl acetate, propyl
acetate, methyl propionate, methyl butyrate, dimethyl malonate, isobutyl
acetate, methylisobutyl ketone, and combinations thereof; removing at
least 50 weight percent, based on the weight of the water immiscible
phase, of the water immiscible solvent from the water immiscible phase
thereby concentrating the cyanohydrin;
(D) adding a water miscible amide solvent to the concentrated cyanohydrin
to form a cyanohydrin solution, wherein the water miscible amide solvent
is selected from the group consisting of N,N-dimethylformamide,
N,N-diethylformamide, N,N-dimethylacetamide, N,N-diethylacetamide,
N,N-dimethylpropionamide, N,N-diethylpropionamide, formamide, and
combinations thereof; and
(E) passing ammonia through the cyanohydrin solution to obtain an
aminoacetonitrile,
provided steps (B), (C), (D), and (E) are conducted at a temperature of
20.degree. C. to 50.degree. C., and further provided that steps (A), (B),
(C), (D), and (E) are conducted in the same reaction vessel wherein the
cyanohydrin is not isolated.
3. A process for preparing aminoacetonitriles comprising the steps of:
(A) reacting an alkali metal cyanide with 3-pyridinecarboxaldehyde at a
temperature of -5.degree. C. to 5.degree. C. in water to form a
cyanohydrin, wherein the alkali metal cyanide is selected from the group
consisting of sodium cyanide and potassium cyanide;
(B) adding a water immiscible solvent to the cyanohydrin formed in Step (A)
to form a two phase system comprising a water immiscible phase containing
the cyanohydrin and an aqueous phase, wherein the water immiscible solvent
is selected from the group consisting of dichloromethane and ethyl
acetate;
(C) removing at least 50 weight percent, based on the weight of the water
immiscible phase, of the water immiscible solvent from the water
immiscible phase thereby concentrating the cyanohydrin;
(D) adding N,N-dimethylformamide to the concentrated cyanohydrin to form a
cyanohydrin solution; and
(E) passing ammonia through the cyanohydrin solution to obtain an
aminoacetonitrile,
provided steps (B), (C), (D), and (E) are conducted at a temperature of
30.degree. C. to 40.degree. C., and further provided the steps (A), (B),
(C), (D), and (E) are conducted in the same reaction vessel wherein the
cyanohydrin is not isolated.
Description
FIELD OF THE INVENTION
This invention relates to a process for preparing aminoacetonitriles in one
vessel. The process involves the steps of: (A) reacting an alkali metal
cyanide with an aldehyde in water to form a cyanohydrin; (B) extracting
the cyanohydrin formed in Step (A) into a water immiscible solvent to form
a two phase system comprising a water immiscible phase containing the
cyanohydrin and an aqueous phase; (C) removing at least 50 weight percent,
based on the weight of the water immiscible phase, of the water immiscible
solvent from the water immiscible phase thereby concentrating the
cyanohydrin; (D) adding a water miscible amide solvent to the concentrated
Cyanohydrin to form a cyanohydrin solution; and (E) passing ammonia
through the cyanohydrin solution to obtain an aminoacetonitrile.
Aminoacetonitriles are important intermediates in the preparation of amino
acids, thiadiazoles, acylaminoacetonitriles, and imidazole derivatives.
BACKGROUND OF THE INVENTION
Aminoacetonitriles have been prepared by reacting aldehydes with alkali
metal cyanides followed by isolation of the cyanohydrin and subsequent
reaction with ammonia in a suitable solvent. Isolation of the cyanohydrin
can be difficult due to the solubility of cyanohydrin in aqueous medium.
Moreover, isolation of the cyanohydrin is inconvenient and increases the
risk of exposure to hydrogen cyanide.
Aminoacetonitriles have also been prepared without isolation of the
cyanohydrin by the Strecker synthesis using an alkali metal cyanide and an
ammonium salt under aqueous conditions. The Strecker synthesis, however,
is not practical in cases where the aminoacetonitriles are subsequently
used under nonaqueous conditions because it is difficult to isolate the
aminoacetonitriles which are unstable and often water soluble.
In contrast, the present inventor has determined that cyanohydrins can be
efficiently extracted into volatile water immiscible solvents such as
ethyl acetate, thus, avoiding the problem of isolating the
aminoacetonitriles. The solvent is removed to give the cyanohydrin,
preferably as an oil, which is dissolved in a water miscible amide solvent
and reacted with ammonia in the same vessel. Amide solvents are relatively
involatile, thus, allowing passage of ammonia to occur over several hours
without incurring significant solvent loss. Furthermore, clean conversion
to the aminoacetonitriles occurs when amide solvents are used. The use of
amide solvents allows the aminoacetonitriles to be converted to important
intermediates such as thiadiazoles and acylamino derivatives. Other
solvents are not as useful in these respects. For example, use of pyridine
or acetonitrile as solvents in the amination step leads to the formation
of by-products.
The process of the present invention for preparing aminoacetonitriles and
thereafter thiadiazole derivatives is represented as follows.
##STR1##
Reagents/solvents: (1) alkali metal cyanide, mineral acid, water, extract
with water immiscible solvent; (2) amide solvent, ammonia; and (3) sulfur
monochloride.
SUMMARY OF THE INVENTION
Accordingly, it is one object of the present invention to provide a process
for preparing aminoacetonitriles.
Accordingly, it is another object of the invention to provide a process for
preparing aminoacetonitriles in one vessel.
These and other objects are accomplished herein by a process for preparing
aminoacetonitriles in one vessel, said process comprising:
(A) reacting an alkali metal cyanide with an aldehyde at a temperature of
-10.degree. C. to 25.degree. C. in water to form a cyanohydrin;
(B) extracting the cyanohydin formed in Step (A) into a water immiscible
solvent having a boiling point of less than 100.degree. C. to form a two
phase system comprising a water immiscible phase containing the
cyanohydrin and an aqueous phase;
(C) removing at least 50 weight percent, based on the weight of the water
immiscible phase, of the water immiscible solvent from the water
immiscible phase thereby concentrating the cyanohydrin;
(D) adding a water miscible amide solvent to the concentrated cyanohydrin
to form a cyanohydrin solution; and
(E) passing ammonia through the cyanohydrin solution to obtain an
aminoacetonitrile.
DESCRIPTION OF THE INVENTION
The process of the present invention for preparing aminoacetonitriles in
one vessel involves five steps. In the first step, Step (A), an alkali
metal cyanide and an aldehyde are reacted at a temperature of -10.degree.
C. to 25.degree. C. in water to form a cyanohydrin. Preferably the alkali
metal cyanide and aldehyde are reacted at a temperature of -5.degree. C.
to 5.degree. C. The alkali metal cyanide is preferably potassium cyanide
or sodium cyanide. The aldehyde has the general formula RCHO and is
characterized by an unsaturated carbonyl group (C.dbd.O). The R group is
selected from hydrogen, unsubstituted or substituted straight chain or
branched C.sub.1 -C.sub.20 alkyl, unsubstituted or substituted C.sub.3
-C.sub.8 cycloalkyl, C.sub.3 -C.sub.8 alkenyl, C.sub.3 -C.sub.8 alkynyl,
and C.sub.6 -C.sub.14 aryl.
The unsubstituted and substituted C.sub.3 -C.sub.8 cycloalkyl groups
mentioned above refer to cycloaliphatic hydrocarbon groups which contain 3
to 8 carbons in the ring, preferably 5 or 6 carbons, and these cycloalkyl
groups substituted with one or two of C.sub.1 -C.sub.4 alkyl, C.sub.1
-C.sub.4 alkoxy, hydroxy or C.sub.1 -C.sub.4 alkanoyloxy.
The C.sub.3 -C.sub.8 alkenyl and C.sub.3 -C.sub.8 alkynyl groups represent
straight or branched chain hydrocarbon radicals containing 3 to 8 carbons
in the chain and which contain a carbon-carbon double bond or a
carbon-carbon triple bond, respectively.
The term "aryl" is used to include carbocyclic aryl groups containing up to
fourteen carbons, e.g., phenyl and naphthyl, and those substituted with
one or two groups selected from C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4
alkoxy, C.sub.1 -C.sub.4 -alkoxycarbonyl, C.sub.1 -C.sub.4 -alkanoyloxy,
C.sub.1 -C.sub.4 -alkanoylamino, halogen, cyano, C.sub.1 -C.sub.4
-alkylsulfonyl, C.sub.1 -C.sub.4 -alkylene-(OH).sub.n, O--C.sub.1 -C.sub.4
-alkylene-(OH).sub.n, --S--C.sub.1 -C.sub.4 -alkylene-(OH).sub.n,
-SO.sub.2 -C.sub.1 -C.sub.4 -alkylene-(OH).sub.n, -CO.sub.2 -C.sub.1
-C.sub.4 -alkylene-(OH).sub.n, SO.sub.2 N(R.sub.17)C.sub.1 -C.sub.4
-alkylene-(OH).sub.n, --SO.sub.2 N(C.sub.1 --C.sub.4 -alkylene-OH).sub.2,
--CON (R.sub.17)C.sub.1 -C.sub.4 -alkylene-(OH).sub.n, --CON (C.sub.1
-C.sub.4 -alkylene-OH).sub.2, --N (SO.sub.2 C.sub.1 -C.sub.4
-alkyl)-alkylene-(OH).sub.n or --N(SO.sub.2 phenyl)-C.sub.1 -C.sub.4
-alkylene-(OH).sub.n ; wherein n is one or two.
The term "aryl" is also used to include heterocyclic aryl groups such as a
5 or 6-membered heterocyclic aromatic ring containing one oxygen atom,
and/or one sulfur atom, and/or up to three nitrogen atoms, said
heterocyclic aryl ring optionally fused to one or two phenyl rings or
another 5 or 6-membered heteroaryl ring. Examples of such ring systems
include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl,
isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl,
tetrazolyl, thiatriazoly, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl,
pyridazinyl, thiazinyl, oxazinyl, triazinyl, thiadiazinyl, oxadiazinyl,
dithiazinyl, dioxazinyl, oxathiazinyl, tetrazinyl, thiatriazinyl,
oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidyl,
tetrahydropyrimidyl, tetrazolo-[1,5-b]pyridazinyl and purinyl,
benzoxazolyl, benzothiazolyl, benzimidazolyl, indolyl, and the like and
those rings substituted with one or more substituents listed above in the
definition of the term "aryl".
In addition, the term "aryl" includes arylene groups. The term "arylene" is
used to represent a divalent carbocylic aryl hydrocarbon moiety containing
up to fourteen carbons, e.g., o-, m- and p-phenylene, and those
substituted with one or two groups selected from C.sub.1 -C.sub.4 -alkyl,
C.sub.1 -C.sub.4 -alkoxy or halogen. Examples of suitable aldehydes for
use in the process of this invention are: p-anisaldehyde,
thiophene-2-carboxaldehyde, furan-2-carboxaldehyde, benzaldehyde,
crotonaldehyde, trimethylacetaldehyde, acetaldehyde, 4-methylbenzaldehyde,
4-N,N-dimethylaminobenzaldehyde, 3-pyridinecarboxaldehyde, valeraldehyde,
and 2-chlorobenzaldehyde. It is important to note that the use of
3-nitrobenzaldehyde as the aldehyde in the process of the present
invention does not result in the desired aminoacetonitrile.
In the second step, Step (B), the cyanohydrin formed in Step (A) is
extracted into a water immiscible solvent to form a two phase system
comprising a water immiscible phase containing the cyanohydrin and an
aqueous phase. The aqueous phase is discarded. The water immiscible
extraction solvent preferably has a boiling point of less than 100.degree.
C. Suitable water immiscible extraction solvents include dichloromethane,
ethyl acetate, diethyl ether, chloroform, 1,2-dichloroetbane, methyl
acetate, propyl acetate, methyl propionate, methyl butyrate, dimethyl
malonate, isobutyl acetate, methylisobutyl ketone, and mixtures thereof.
Dichloromethane and ethyl acetate are the preferred water immiscible
solvents. It is not unusual to repeat the extraction. It should be noted
that toluene and heptanes are not efficient solvents for the extraction of
the cyanohydrin.
In the third step, Step (C), at least 50 weight percent of the water
immiscible solvent, based on the weight of the water immiscible phase, is
removed by distillation at atmospheric or reduced pressure from the water
immiscible phase thereby concentrating the cyanohydrin. Preferably, at
least 90 weight percent of the water immiscible solvent is removed from
the water immiscible phase. Most preferably, the cyanohydrin is
concentrated to the degree that it is essentially free from water
immiscible solvent. For the most part, any water immiscible solvent
remaining with the cyanohydrin will be volatilized upon passage of ammonia
in Step (E) supra.
In the fourth step, Step (D), a water miscible amide solvent is added to
the concentrated cyanohydrin from Step (C) to form a cyanohydrin solution.
Suitable water miscible amide solvents for use in the processes of the
present invention are: N,N-dimethylformamide, N,N-diethylformamide,
N,N-dimethylacetamide, N,N-diethylacetamide, N,N-dimethylpropionamide,
N,N-diethylpropionamide and formamide. The water miscible amide solvent
may also include a combination of such solvents. The use of pyridine or
acetonitrile as solvents in the amination step leads to the formation of
by-products.
In the fifth step, Step (E), ammonia is passed through the cyanohydrin
solution from Step (D) to obtain an aminoacetonitrile. Steps (B), (C),
(D), and (E) are conducted at a temperature from 20.degree. C. to
50.degree. C. A preferred temperature range is 30C. to 40C. Although
higher temperatures may be employed, there is no advantage to conducting
these reactions at higher temperatures. Moreover, at temperatures above
50C., the aminolysis reaction requires the use of pressurized equipment.
The aminoacetonitriles are important intermediates in the preparation of
amino acids, thiadiazoles, acylaminoacetonitriles, and imidazole
derivatives. It is important to note, however, that aminoacetonitriles
containing primary and secondary alkyl groups are not useful when the
desired product is a thiadiazole. For example, where the aminoacetonitrile
contains an n-butyl group, reaction with sulfur monochloride results in a
complex mixture which does not contain any thiadiazole. Sulfur
monochloride may be reacted with the aminoacetonitriles to obtain
3-chloro-4-substituted-1,2,5-thiadiazoles which are useful as
intermediates in the synthesis of M1 selective muscarinic agonists,
analgesics, antiglaucoma drugs and for treating Alzheimer's disease.
Alternatively, the aminoacetonitriles may be reacted with heterocyclic
acid chlorides to obtain carboxamide derivatives which are useful as
intermediates for agrochemical fungicides and microbicides.
Examples of agrochemical carboxamide intermediates derived from
aminoacetonitriles include:
##STR2##
The process of the present invention will be further illustrated by a
consideration of the following examples, which are intended to be
exemplary of the invention. All parts and percentages in the examples are
on a weight basis unless otherwise stated.
EXAMPLE I
Preparation of 3-(4-CHLORO-1,2,5-THIADIAZOL-3-YL) PYRIDINE
##STR3##
Reagents/Solvents
1. Potassium cyanide, water, 11.6M-hydrochloric acid, ethyl acetate;
2. N,N-dimethylformamide (DMF), ammonia (excess); and
3. Sulfur monochloride.
EXAMPLE II
Preparation of 2-Hydroxy-2(3-pyridinyl)acetonitrile.
11.6M-Hydrochloric acid (18 ml, 21.6 g, 0.2 mole) and 17 ml water were
added to a 200 ml three necked flask equipped with an overhead stirrer,
thermometer and dropping funnel. The solution was cooled to 0.degree. C.
and 97% 3-pyridinecarboxaldehyde (21.4 g, 0.2 mole) was added. The mixture
was cooled to -5.degree. C. to give a slurry of pyridinecarboxaldehyde
hydrochloride. A solution of potassium cyanide (14.32 g, 0.22 mole) and 40
grams of water was added dropwise to the stirred mixture over 30 minutes,
during which the temperature was maintained at -5.degree. C. to -1.degree.
C. During the addition a yellow solution was obtained after approximately
half the cyanide solution has been added but a slurry is again formed
towards the end of the addition. The reaction was mildly exothermic.
Stirring was continued for one hour after the addition was complete.
1M-hydrochloric acid (1 ml) was added to bring the mixture to pH 7. Ethyl
acetate (70 ml) was added and the mixture warmed to 10.degree. C.
whereupon two clear layers were obtained. A 0.5 ml sample of the ethyl
acetate layer was removed and evaporated to give a white solid with a
melting point of 71.degree. to 73.degree. C. An NMR spectrum was
consistent with the desired cyanohydrin.
The bottom aqueous layer was run off and treated with bleach before
discarding. Ethyl acetate was removed at reduced pressure (65mm) over 30
minutes using an oil bath set at 70.degree. C. to give a mobile paste. The
NMR spectrum (DMF/CDCl.sub.3) of the paste was consistent with the desired
product (CH at d=5.7) and showed that no aldehyde starting material was
present. This implies that the yield of the product is quantitative. The
product was dissolved in N,N-dimethylformamide and treated with ammonia.
EXAMPLE III
Preparation of 2-Amino-2-(3-pyridil)acetonitrile
N,N-Dimethylformamide (100 ml) was added to the paste to give a pale yellow
solution. Ammonia was passed, via a sintered glass tube, through the
solution for 68 hours at 25.degree. C. to give a reddish orange solution
of the aminonitrile. The mixture was periodically analyzed by NMR
spectroscopy. The temperature rose initially from 24.degree. C. to
34.degree. C. and the mixture became a deeper yellow color.
NMR analysis showed that very little cyanohydrin (CH at 5.7 ppm) remained
after 44 hours (product CH at 5.1 ppm) . However several other smaller
signals close to 5.1 ppm were also observed during this time hut
disappeared after 68:hours. One of the smaller signals may he due to the
CH of the deprotonated cyanohydrin. Excess ammonia was removed at 65 mm by
application of water pump pressure for 1 hour.
EXAMPLE IV
Preparation of 3-(4-chloro-1,2,5-thiadiazol-3-YL)pyridine
Supercell T (10 g) was added to the solution of aminonitrile prepared in
Example 3 (assume 0.18 mole) in DMF (approx. 100 ml), in a 200 ml flask.
(Supercell T was added to prevent the coagulation of the sulfur formed
during the reaction involving sulfur monochloride). The mixture was cooled
to -15.degree. C. and sulfur monochloride (49 g, 29 ml, 0.36 mole) was
added dropwise with stirring over 40 minutes, so that the temperature was
maintained at -10.degree. to -3.degree. C. An acetone/solid carbon dioxide
bath was used.
The reaction was very exothermic particularly during addition of the first
25% of the sulfur monochloride which required 1 hour in order to keep the
temperature at -5.degree. to 0.degree. C. The mixture was cooled to
0.degree. C. and ice cold water (100 g) was added over 15 minutes. The
mixture was stirred for 12 hours. Sulfur and supercell T were removed by
filtration into a 500 ml flask and the residue washed with 20 grams of
water. The damp residue weighed 42 grams. The combined filtrates were
cooled to 0.degree. C. and toluene (100 ml, water (87 g) was added. A
mixture of sodium hydroxide (27 g, 0.675 mole) and water (27 g) was added
over 15 minutes, keeping the temperature at 10.degree. to 15.degree. C. to
bring the mixture to pH 9. Supercell T (10 g) and water (50 g) were added
and the mixture was stirred for 15 minutes and then partially filtered
back into the original 200 ml flask.
The bottom aqueous layer was run off and discarded. (A flashlight is useful
for detecting the interface between the two dark layers). The remaining
material in the 500 ml flask was filtered into a 200 ml flask and the
layers were separated as before. The total aqueous solution discarded was
300 ml. Extraction of this solution with toluene (50 ml) and evaporation
of the toluene gave only a further 1 g product. The residue was washed
with toluene (20 ml, 17.3 g). The combined filtrates were washed with 50
grams of water and the lower aqueous layer (53 g) was discarded. The upper
toluene layer (120 g, approx. 138 ml) was evaporated at 45.degree. C. at
reduced pressure to give 20 grams of crude product which appeared as a
brownish orange oil.
Heptanes (150 ml, 102 g) was added to the oil and the mixture stirred and
heated to 45.degree. C. After 30 minutes, the clear yellow supernatent was
filtered into the 500 ml flask to remove 2 grams of a dark brown insoluble
residue. The heptanes solution was transferred back to a clean 200 ml
flask and evaporated under reduced pressure at 45.degree. C. to give 17
grams of an orange oil which crystallized on cooling. Thin layer
Chromatography showed that most of the impurities which had lower Rfs than
the product had been removed. An NMR spectrum was consistent with the
desired product + solvents (heptanes, toluene, DMF). HPLC indicated that
the product was 98.5% pure.
The product was dissolved in methanol (30 ml) at 30.degree. C. to give a
clear solution which was then cooled to 20.degree. C. (The supercell
treatments used in this experiment appear to effectively remove the sulfur
and make filtration at this stage, unnecessary). Water (60 ml) was added
dropwise with stirring until a permanent cloudiness was obtained. The
mixture was seeded and stirring continued until crystallization began.
Stirrer speed was increased and the remaining water added more rapidly.
The solid was collected and washed with 15 grams water which had been used
to rinse out the flask.
The solid material, 28 grams, was dried under vacuum for 48 hours at
30.degree. C. to give 99% pure 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine
(16 g, 45% yield) as a pale yellow solid with a melting point of
51.degree. to 52C. NMR data was as follows: (CDCl.sub.3, ppm) 7.46 (dd,
1H), 8,29 (dt, 1H), 8.75 (dd, 1H), 9,24 (d, 1H).
Many variations will suggest themselves to those skilled in this art in
light of the above detailed description. All such obvious modifications
are within the full intended scope of the appended claims.
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